Intercellular communication within the virus microenvironment affects the susceptibility of cells to secondary viral infections

Communication between infected cells and cells in the surrounding tissue is a determinant of viral spread. However, it remains unclear how cells in close or distant proximity to an infected cell respond to primary or secondary infections. We establish a cell-based system to characterize a virus microenvironment, distinguishing infected, neighboring, and distal cells. Cell sorting, microscopy, proteomics, and cell cycle assays allow resolving cellular features and functional consequences of proximity to infection. We show that human cytomegalovirus (HCMV) infection primes neighboring cells for both subsequent HCMV infections and secondary infections with herpes simplex virus 1 and influenza A. Neighboring cells exhibit mitotic arrest, dampened innate immunity, and altered extracellular matrix. Conversely, distal cells are poised to slow viral spread due to enhanced antiviral responses. These findings demonstrate how infection reshapes the microenvironment through intercellular sig- naling to facilitate spread and how spatial proximity to an infection guides cell fate.

Automated summary

Communication between infected cells and cells in the surrounding tissue is crucial for viral spread. A cell-based system was established to investigate the virus microenvironment and the responses of neighboring and distal cells to primary or secondary infections. The study reveals that human cytomegalovirus (HCMV) infection primes neighboring cells for subsequent HCMV infections and secondary infections with herpes simplex virus 1 and influenza A, while distal cells exhibit enhanced antiviral responses to slow down viral spread. These findings highlight the importance of intercellular signaling and spatial proximity in shaping the microenvironment and determining cell fate during infections.